G Model
CCLET 5342 No. of Pages 5
Chinese Chemical Letters
Communication
Thiazolylhydrazone dervatives as inhibitors for insect
N-acetyl-β- -hexosaminidase and chitinase
D
Huibin Yanga,b,1, Huitang Qic,1, Zesheng Haob, Xusheng Shaoa, Tian Liuc, Qing Yangc,
,
*
Xuhong Qiana,
*
a
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
b
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals Research and Development Co., Ltd., Shenyang
110021, China
c
School of Bioengineering, Dalian University of Technology, Dalian 116024, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Insect chitinase and N-acetyl-β-D-hexosaminidases (Hex) are potential targets for developing new
Received 8 October 2019
Received in revised form 18 November 2019
Accepted 20 November 2019
Available online xxx
pesticides. Here, a series of thiazolylhydrazones I (with substituted group R1 at N3) and II (with
substituted group R1 at N2) were designed, synthesised and evaluated as competitive inhibitors of
OfHex1and OfChi-h, from the agricultural pest Ostrinia furnacalis. Derivatives I-3d and II-3d, with
phenoxyethyl group at R1, demonstrated the best inhibitory activities against OfHex1 and OfChi-h.
Molecular docking analysis indicated that the branched conformation compound II-3d (Ki = 1.5
formed more hydrogen bonds with OfHex1 than the stretched conformation compound I-3d
(Ki = 5.9 mol/L). The differences in compounds’ binding conformations with OfChi-h explained
differences in inhibitory activity of compounds I-3d (Ki = 1.9 mol/L) and II-3d (Ki = 4.1 mol/L). This
work suggests a novel scaffold for developing specific Hex and Chi-h inhibitors.
mmol/L)
Keywords:
N-acetyl-β-
Chitinase
Inhibitor
Chitin
D-hexosaminidase
m
m
m
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Structure-activity relationship
Thiazolylhydrazone derivatives
Molecular docking
Heterocyclic compounds are an important role building block in
medicinal chemistry. Thiazolidinones have been extensively
investigated over recent decades for a varied range of biological
activities, including antifungal [1], antiparasitic [2], antimicrobial
[3], antioxidant [4], anticonvulsant [5], anti-HIV [6], anti-inflamma-
tory [7], anti-tuberculosis [8], and anti-tumour activities [9].
Thiazolylhydrazone derivatives, with a R1R2C = N-N = substituent
in the 2-position of thiazolidin-4-one, have been studied for their
biological properties, such as antiparasitic [2,10], antifungal [11],
antiurease [12] and antiviral activities [13].
(Hex; EC 3.2.1.52) [18], cooperate with each other to facilitate the
degradation of chitin. The chitinase can act on random positions of
the chitin polymer chain to produce chitooligosaccharides [19,20],
while Hex is responsible for hydrolyzing chitooligosaccharides to
N-acetyl-D-glucosamine during chitin degradation [18,21]. Be-
cause of the absence of chitin from vertebrates and higher plants,
small molecules inhibitors against chitinase and Hex are promising
potential targets for pesticide development.
Reported GH20 inhibitors have varied chemical structures.
Some are carbohydrate-based inhibitors, such as DNJNAc and its
derivatives [22–25], GDL and its derivative PUGNAC [26–29], NTA-
glucal [30], 6-Ac-CAS [31,28], NAG-thiazoline and its derivative
NMAGT [32,33], LNB-thiazoline [34] and TMG-chitotriomycin [35].
Non-carbohydrate-based GH20 inhibitors include naphthalimides
[36], pyrimethamine and its derivatives [37]. Small molecules
against GH18 chitinases have been reported. The pseudotrisac-
charide allosamidin isolated from the Streptomyces sp. [38],
cyclopentapeptides argifin isolated from Gliocladium sp. FTD-
0668 [39], argadin isolated from Clonostachys sp. FO-7314 [40],
Chitin, a linear homopolymer of N-acetyl-β-D-glucosamines and
a major structural component of insect cuticles, plays an important
role in the molting [14–16]. In the degradation system of insect
chitin, two glycoside hydrolase family members, the glycosyl
hydrolase family 18 (GH18) chitinase (EC 3.2.1.14) [17] and the
glycosyl hydrolase family 20 (GH20) β-N-acetylhexosaminidase
* Corresponding authors.
cyclo(L-Arg-D-Pro) from Pseudomonas sp. IZ208 [41], chitobiose and
chitotriose thiazolines [42], xanthine derivatives [43], and CI-4
[44,45], all exhibit effective inhibitory activities. However, it is
(X. Qian).
1
These authors contributed equally to this work.
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: H. Yang, et al., Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-D-hexosaminidase and